Enhanced lipid uptake: A novel metabolic target to fight the adaptive response to androgen-targeted therapies in prostate cancer

Prostate cancer (PCa) is the most commonly diagnosed cancer among men and is the second leading cause of cancer related death in men worldwide. Current treatments of advanced PCa target the Androgen Receptor (AR), a transcription factor that controls the expression of a large set of genes associated with metabolism, survival and growth of PCa cells. Despite initial disease regression following AR-targeted therapies (ATT) with androgen deprivation and AR-antagonists, almost all patients develop recurrent disease and progress to castrate-resistant PCa (CRPC). Our objective is to characterise and develop therapies against the adaptive response to ATT, fighting the progression to lethal CRPC. We discovered that PCa cells and tumour xenografts treated with ATT increased lipid uptake. Lipid supply through de novo lipogenesis of cholesterol and fatty acids is well-known AR-regulated pathway in PCa and a metabolic hallmark of cancer. However, our understanding of lipid supply from exogenous sources through lipid uptake is very limited in PCa. Here, we show that ATT-induced lipid supply stress increases cellular lipid content, lipid uptake and the expression of lipid transporters and induces the expression of tunnelling nanotubes mediating cell-cell transfer of cytoplasmic material, including lipid droplets and mitochondria. Furthermore, we present strategies that target lipid uptake and generate lipid supply stress with repurposed drugs. In summary, co-inhibition of AR and enhanced lipid uptake is a novel therapeutic concept of targeting the adaptive response to ATT in advanced PCa.